New method for the treatment of inflammatory diseases

Abstract

The present invention relates to the use of an inhibitor of the formation of nicotinamide adenyl dinucleotide for the preparation of a medicament used in the treatment of inflammatory diseases such as rheumatoid arthritis and endotoxemia.

1 . Method of treating inflammatory diseases comprising administering to a subject an effective amount of an inhibitor of the formation of nicotinamide adenyl dinucleotide. 
   
   
       2 . Method according to  claim 1 , wherein the inhibitor is a noncompetitive or competitive inhibitor of the enzyme nicotinamide phosphoribosyltransferase. 
   
   
       3 . Method according to  claim 1 , wherein the inhibitor is a compound according to formula (I): 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -cycloalkyl, C 1 -C 4 -hydroxyalkyl, hydroxy, C 1 -C 4 -alkoxy, benzyloxy, C 1 -C 4 -alkanoyloxy, C 1 -C 4 -alkylthio, C 2 -C 5 -alkoxycarbonyl, aminocarbonyl, C 3 -C 8 -dialkylaminocarbonyl, carboxy, phenyl, phenoxy, pyridyloxy, and NR 5 R 6 , wherein 
       R 5  and R 6  are selected independently from each other from hydrogen and C 1 -C 6 -alkyl, 
       R 2  is selected from hydrogen, halogen, C 1 -C 6 -alkyl, trifluoromethyl and hydroxy, wherein 
       R 1  and R 2 , in the case they are adjacent, optionally form a bridge which is selected from the group of bridge members —(CH 2 ) 4 — and —(CH═CH) 2 — and —CH 2 O—CR 7 R 8 —O—, wherein 
       R 7  and R 8  are independent from each other, hydrogen or C 1 -C 6 -alkyl, 
       R 3  is selected from hydrogen, halogen and C 1 -C 6 -alkyl, 
       R 4  is selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, hydroxy, C 1 -C 6 -alkoxy and benzyloxy, 
       k is 0 or 1, 
       A is selected from
 C 2 -C 6 -alkenylene, which is optionally substituted one to three-fold by C 1 -C 3 -alkyl, hydroxy, fluorine, cyano, or phenyl, 
 C 4 -C 6 -alkadienylene, which is optionally substituted once or twice by C 1 -C 3 -alkyl, fluorine, cyano, or phenyl, 
 1,3,5-hexatrienylene, which is optionally substituted by C 1 -C 3 -alkyl, fluorine, or cyano, and ethinylene, 
 
       D is selected from
 C 1 -C 10 -alkylene, optionally substituted once or twice by C 1 -C 3 -alkyl or hydroxy, 
 C 2 -C 10 -alkenylene, optionally substituted once or twice by C 1 -C 3 -alkyl or hydroxy, wherein the double bond optionally is to ring E. 
 C 3 -C 10 -alkinylene, optionally substituted once or twice by C 1 -C 3 -alkyl or hydroxy, and 
 the group consisting of C 1 -C 10 -alkylene, C 2 -C 10 -alkenylene and C 3 -C 10 -alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR 9 , CO, SO or SO 2 , wherein 
 R 9  is selected from hydrogen, C 1 -C 3 -alkyl, C 1 -C 6 -acyl and methanesulfonyl, 
 
       E is selected from 
     
     
       
         
         
             
             
         
       
       
         wherein the heterocyclic ring optionally has a double bond and 
       
       n and p are, independent of each other, 0, 1, 2 or 3, with the proviso that n+p≦4, 
       q is 1 or 2, 
       R 10  is selected from hydrogen, C 1 -C 3 -alkyl, hydroxy, and hydroxymethyl, carboxy and C 2 -C 7 -alkoxycarbonyl, 
       R 11  xis hydrogen or an oxo group adjacent to the nitrogen atom, 
       G is selected from hydrogen,
 G1, G2, G3, G4 and G5, wherein 
 
       G1 represents the residue
   —(CH 2 ) r —(CR 13 R 14 ) s —R 12   (G1) 
 wherein 
 
       r is 0, 1 or 2 and 
       s is 0 or 1, 
       R 12  is selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkinyl, C 3 -C 8 -cycloalkyl, benzyl, phenyl,
 the group consisting of monocyclic aromatic five- and six-membered heterocycles, which contain one to three hetero-atoms selected from N, S and O and are either bound directly or over a methylene group, 
 the group consisting of anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group, and 
 the group consisting of anellated bi- and tricyclic aromatic or partially hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms are selected from N, S and O and the bond occurs either over an aromatic or a hydrogenated ring, and either directly or over a methylene group, 
 
       R 13  has the same meaning as R 12 , but is selected independently thereof, 
       R 14  is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
 the group consisting of monocyclic aromatic five- and six-membered heterocycles, which contain one to three hetero-atoms selected from N, S and O and are bound either directly or over a methylene group, 
 the group consisting of anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group, and 
 the group consisting of anellated bi- and tricyclic aromatic or partially hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms are selected from N, S and O and the bond occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group, 
 
       G2 is selected from the residues 
     
     
       
         
         
             
             
         
       
       
         wherein the substituents R 12  and R 14  have the above meaning, or the group
   —NR 12 R 14    
 
         is a nitrogen-containing heterocycle bound over the nitrogen atom, the nitrogen-containing heterocycle being selected from 
         the group consisting of saturated and unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, 
         optionally contain one or two further hetero-atoms selected from N, S and O, and the group consisting of saturated and unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, optionally contain one or two further hetero-atoms selected from N, S and O, 
       
       G3 is the residue
   —SO 2 —(CH 2 ) r R 12   (G5) 
 
       G4 is the residue 
     
     
       
         
         
             
             
         
       
       wherein 
       Ar 1  and Ar 2  are selected independently of each other from phenyl, pyridyl and naphthyl, 
       G5 is the residue
   —COR 15   (G5) 
 wherein 
 
       R 15  is selected from trifluoromethyl, C 1 -C 6 -alkoxy, C 3 -C 6 -alkenyloxy and benzyloxy, 
       wherein aromatic ring systems in the substituents R 1 , R 2 , R 4 , R 12 , R 13 , R 14 , R 15 , Ar 1  and Ar 2  and in the ring system —NR 12 R 14  optionally carry independently of each other one to three substituents which are independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -cycloalkyl, phenyl, benzyl, hydroxy, 
       C 1 -C 6 -alkoxy, which is optionally entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C 1 -C 6 -alkylthio, carboxy, C 1 -C 6 -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C 1 -C 6 -alkylamino, and di-(C 1 -C 6 -alkyl)-amino, 
       wherein two adjacent groups of the aromatic ring or ring system optionally form an additional ring over a methylenedioxy bridge, 
       tautomeres in the case of substitution of the heterocycle or in an anellated ring system by free hydroxy, mercapto and/or amino groups, 
       stereoisomers and/or mixtures thereof and pharmacologically acceptable acid addition salts with the exception of (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride. 
     
   
   
       4 . Method according to  claim 3 , wherein:
 R 1  is selected from hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy, and phenoxy,   R 2  is selected from hydrogen, halogen, trifluoromethyl and hydroxy,   R 3  is hydrogen or halogen,   R 4  is selected from hydrogen, C 1 -C 3 -alkyl, hydroxy and C 1 -C 3 -alkoxy,   k is 0 or 1,   A is selected from C 2 -C 6 -alkenylene, optionally substituted once or twice by C 1 -C 3 -alkyl, hydroxy or fluorine,
 C 4 -C 6 -alkadienylene, optionally substituted by C 1 -C 3 -alkyl or by 1 or 2 fluorine atoms, and 1,3,5-hexatrienylene, optionally substituted by fluorine, 
   D is selected from C 1 -C 8 -alkylene, optionally substituted once or twice by methyl or hydroxyl,
 C 2 -C 8 -alkenylene, optionally substituted once or twice by methyl or hydroxy, wherein the double bond optionally is to ring E, 
 C 3 -C 8 -alkinylene optionally substituted once or twice by methyl or hydroxy, and the group consisting of C 1 -C 8 -alkylene, C 2 -C 8 -alkenylene and C 3 -C 8 -alkinylene in which one to three methylene units are isosterically replaced by O, S, NH, N(CH 3 ), N(COCH 3 ), N(SO 2 CH 3 ) CO, SO or SO 2 , 
   E is selected from   
     
       
         
         
             
             
         
       
       
         wherein the heterocyclic ring optionally has a double bond and 
       
       n and p are, independent of each other, 0, 1, 2 or 3, with the proviso that n+p≦3, 
       q is 1 or 2, 
       R 10  is selected from hydrogen, C 1 -C 3 -alkyl, hydroxy, and hydroxymethyl, 
       R 11  is hydrogen or an oxo group which is adjacent to the nitrogen atom, 
       G is selected from hydrogen,
 G1, G2, G3, G4 and G5, wherein 
 
       G1 represents the residue
   —(CH 2 ) r —(CR 13 R 14 ) s —R 12   (G1) 
 wherein 
 
       r is 0, 1 or 2 and 
       s is 0 or 1, 
       R 12  is selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, benzyl, phenyl,
 the group consisting of benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dihydrophenanthryl, oxodihydrophenanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl and oxotetrahydrodibenzocyclooctenyl, bound directly or over a methylene group, 
 and 
 the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, oxodihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl, and oxodihydropyridobenzothiazepinyl, bound directly or over a methylene group, 
 
       R 13  has the same meaning as R 12 , but is selected independently therefrom, 
       R 14  is selected from hydrogen, hydroxy, methyl, benzyl, phenyl, and,
 the group consisting of indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl, and tetrahydroquinolyl, bound directly or over a methylene group, 
 
       G2 is selected from the residue 
     
     
       
         
         
             
             
         
       
       
         wherein the substituents R 12  and R 14  have the above meanings, or the group
   —NR 12 R 14    
 
         is a nitrogen-containing heterocycle bound over the nitrogen atom, the nitrogen-containing heterocycle being selected from the group consisting of azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholine-1,1-dioxide, 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]-heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 9-azabicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tet-rahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine, and (5H)-tetrahydrodibenzazocine, 
       
       G3 is the residue
   —SO 2 —(CH 2 ) r R 12   (G3), 
 
       G4 is the residue 
     
     
       
         
         
             
             
         
       
       
         wherein 
       
       Ar 1  and Ar 2  are selected independently of each other from phenyl, pyridyl, and naphthyl, 
       G5 is the residue
   —COR 15   (G5) 
 wherein 
 
       R 15  is selected from trifluoromethyl, C 1 -C 6 -alkoxy, C 3 -C 6 -alkenyloxy, and benzyloxy, 
       wherein aromatic ring systems optionally are substituted independently of each other by one to three substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -cycloalkyl, phenyl, benzyl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy entirely or partially substituted by fluorine; benzyloxy, 
       phenoxy, mercapto, C 1 -C 6 -alkylthio, carboxy, C 1 -C 6 -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C 1 -C 6 -alkylamino, and di-(C 1 -C 6 -alkyl)-amino,
 wherein two adjacent groups in the ring or ring system optionally form an additional ring over a methylenedioxy bridge. 
 
     
   
   
       5 . Method according to  claim 3 , wherein:
 R 1  is selected from hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, methoxy and methoxycarbonyl,   R 2  is hydrogen or halogen,   R 3  is hydrogen,   R 4  is selected from hydrogen, C 1 -C 3 -alkyl and hydroxy,   k is 0 or 1,   A is selected from C 2 -C 6 -alkenylene, optionally substituted once or twice by hydroxy or fluorine, or C 4 -C 6 -alkadienylene, optionally substituted by one or two fluorine atoms, and 1,3,5-hexatrienylene   D is selected from C 2 -C 8 -alkylene, optionally substituted by methyl or hydroxy C 2 -C 8 -alkenylene, optionally substituted by methyl or hydroxy, wherein the double bond optionally is to ring E, and
 the group consisting of C 2 -C 8 -alkylene and C 2 -C 8 -alkenylene, wherein one to three methylene units are isosterically replaced by O, NH, N(CH 3 ), N(COCH 3 ), N(SO 2 CH 3 ) or CO, 
   E is selected from the residues   
     
       
         
         
             
             
         
       
       
         wherein the heterocyclic ring optionally has a double bond and 
       
       n and p are, independent of each other, 0, 1, 2 or 3, with the proviso that n+p≦3 
       q is 1 or 2, 
       R 10  is selected from hydrogen, methyl and hydroxyl, 
       R 11  is hydrogen or an oxo group adjacent to the nitrogen atom, 
       G is selected from hydrogen, C 3 -C 8 -cycloalkyl, methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, diphenylphosphinoyl and the residues
   —(CH 2 ) r —(CR 13 R 14 ) s R 12   (G1) 
 
     
     
       
         
         
             
             
         
       
       
         and
   —SO 2 —(CH 2 ) r R 12   (G3) 
 
         wherein 
       
       r is 0, 1 or 2, 
       s is 0 or 1, 
       R 12  is selected from hydrogen, methyl, benzyl, phenyl.
 the group consisting of indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, flourenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, and oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl bound directly or over a methylene group, and 
 the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, 
 benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzoxepinyl, dihydrodibenzothiazepinyl, and oxodihydrodibenzothiazepinyl, bound directly or over a methylene group, 
 
       R 13  is selected from hydrogen, methyl, benzyl and phenyl, 
       R 14  is selected from hydrogen, hydroxy, methyl, benzyl, phenyl, and
 the group consisting of naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzim-idazolyl, chromanyl, quinolyl and tetrahydroquinolyl, bound directly or over a methylene group, wherein in formula 
 
     
     
       
         
         
             
             
         
       
       
         —NR 12 R 14  optionally is selected from pyrrolidine, piperidine, (1H)-tetrahydropyridine, hexahydroazepine, octahydroazocine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine and (5H)-tetrahydrodibenzazocine 
       
     
   
   
       6 . Method according to  claim 3 , wherein:
 R 1  is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl and hydroxy,   R 2  and R 3  are hydrogen,   R 4  is hydrogen or hydroxy,   k is 0 or 1,   A is C 2 -C 4 -alkenylene, which is optionally substituted by fluorine,   D is selected from C 2 -C 6 -alkylene, C 2 -C 6 -alkenylene, wherein the double bond optionally is to ring E, and the group consisting of C 2 -C 6 -alkylene and C 2 -C 6 -alkenylene, wherein a methylene unit is isosterically replaced by O, NH, N(CH 3 ) or CO, or an ethylene group is isosterically replaced by NH—CO
 or CO—NH, or a propylene group is isosterically replaced by NH—CO—O or O—CO—NH, 
   E is selected from pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally is substituted by an oxo group adjacent to the nitrogen atom,   G is selected from hydrogen, tert-butoxycarbonyl, diphenylphosphinoyl, and one of the residues
   —(CH 2 ) r —(CR 13 R 14 ) S —R 12   (G1) 
   
     
       
         
         
             
             
         
       
       
         and
   —SO 2 —(CH 2 ) r R 12   (G3) 
 
         wherein 
       
       r is 0 or 1, 
       s is 0 or 1, 
       R 12  is selected from hydrogen, methyl, benzyl, phenyl.
 the group consisting of indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, flourenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl and dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, bound directly or over a methylene group, and 
 the group consisting of furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl, 
 benzofuryl, benzothienyl, indolyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, and dihydrodibenzothiazepinyl, bound directly or over a methylene group, 
 
       R 13  is selected from hydrogen, methyl, benzyl and phenyl, 
       R 14  is selected from hydrogen, hydroxy, methyl, benzyl, phenyl, and
 the group consisting of naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl and tetrahydroquinolyl, bound directly or over a methylene group, wherein in the formula 
 
     
     
       
         
         
             
             
         
       
       
         —NR 12 R 14  optionally is selected from pyrrolidine, piperidine, hexahydroazepine, morpholine, 2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]oxazepine, and (11H)-dihydrodibenzo[b,e]thiazepine, 
       
       wherein aromatic ring systems optionally are substituted, independently of each other, by one to three substituents which are independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -cycloalkyl, phenyl, benzyl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy which is entirely or partially substituted by fluorine; 
       benzyloxy, phenoxy, mercapto, C 1 -C 6 -alkylthio, carboxy, C 1 -C 6 -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C 1 -C 6 -alkylamino and di-(C 1 -C 6 -alkyl)-amino, wherein two adjacent groups on the aromatic ring or ring system optionally form an additional ring over a methylenedioxy bridge. 
     
   
   
       7 . Method according to  claim 3 , wherein:
 R 1  is selected from hydrogen, fluorine, methyl, trifluoromethyl and hydroxy,   R 2  and R 3  are hydrogen,   R 4  is hydrogen or hydroxy,   k is 0,   A is ethenylene or 1,3-butadienylene   D is C 2 -C 6 -alkylene or C 2 -C 6 -alkenylene, wherein the double bond optionally is to ring E,   E is selected from pyrrolidine, piperidine, hexahydroazepine and morpholine,   G is selected from benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl, dihydrodibenzocycloheptenyl, furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl, benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl phenyl-pyridylmethyl, dihydrodibenzoxepinyl, dihydrodibenzothiepinyl,
 acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroanthrylcarbonyl, dioxodihydroanthrylcarbonyl, furoyl, pyridylcarbonyl, chromonylcarbonyl, quinolylcarbonyl, 
 naphthylaminocarbonyl, dibenzylaminocarbonyl, benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl, dihydrodibenzazepin-N-carbonyl, tetrahydroquinolinyl-N-carbonyl, tetrahydrobenzo[b]azepinyl-N-carbonyl, 
 methanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, quinolinsulfonyl, and diphenylphosphinoyl, 
   wherein aromatic ring systems optionally are substituted independently of each other by one to three substituents which are independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -cycloalkyl, phenyl, benzyl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy, entirely or partially substituted by fluorine; benzyloxy, phenoxy, mercapto, C 1 -C 6 -alkylthio, carboxy, C 1 -C 6 -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C 1 -C 6 -alkylamino and di-(C 1 -C 6 -alky)-amino, wherein two adjacent groups in the ring or ring system optionally form an additional ring over a methylenedioxy bridge.   
   
   
       8 . Method according to  claim 1 , wherein the inhibitor is a compound selected from 
     N-[4-(1-methylsulfonylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide, 
     N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, 
     N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-5-(pyridin-3-yl)-2,4-pentadienoic acid amide, 
     N-{4-[1-(1-naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, 
     N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide, 
     N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide, 
     N-{4-[1-(10,11-dihydrodibenzo[b,f]azepin-5-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, and 
     N-[4-(1-diphenylphosphinoyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide
 or as a pharmaceutically acceptable acid addition salt thereof. 
 
   
   
       9 . Method according to  claim 1 , wherein the inhibitor is a compound selected from 
     N-[4-(1-acetylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide, 
     N-[4-(1-diphenylacetyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide, 
     N-{4-[1-(3,3-diphenylpropionyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, 
     N-[4-(1-benzoylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide, 
     N-[4-(1-benzoylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide, and N-{4-[1-(9-oxo-9H-fluoren-4-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, or as a pharmaceutically acceptable acid addition salt thereof. 
   
   
       10 . Method according to  claim 1 , wherein the inhibitor is a compound selected from 
     N-{4-[1-(phenylpyridin-3-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, 
     N-{4-[1-(phenylpyridin-4-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide, 
     N-{4-[1-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide and 
     N-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
 or as a pharmaceutically acceptable acid addition salt thereof. 
 
   
   
       11 . Method according to  claim 1 , wherein the inhibitor is a compound selected from 
     N-[7-(1-diphenylmethylpiperidin-4-yl)-heptyl]-3-(pyridin-3-yl)-acrylamide, 
     N-[8-(1-diphenylmethylpiperidin-4-yl)-octyl]-3-(pyridin-3-yl)-acrylamide, 
     N-[3-(1-diphenylmethylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide, and 
     N-[3-(1-benzylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide
 or as a pharmaceutically acceptable acid addition salt thereof. 
 
   
   
       12 . Method according to  claim 1 , wherein the inhibitor is a compound selected from 
     N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide, 
     N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide, 
     N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide and 
     N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide
 or as a pharmaceutically acceptable acid addition salt thereof. 
 
   
   
       13 . Method according to  claim 1 , wherein the inhibitor is (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridine-3-yl)acrylamide. 
   
   
       14 . Method according to  claim 1 , wherein the inflammatory disease is rheumatoid arthritis. 
   
   
       15 . Method according to  claim 1 , wherein the inflammatory disease is endotoxemia. 
   
   
       16 . A pharmaceutical kit comprising at least an effective amount of an inhibitor of the formation of nicotinamide adenyl dinucleotide together with instructions for use in the treatment of inflammatory diseases. 
   
   
       17 . A pharmaceutical kit according to  claim 16 , comprising instructions for use in the treatment of rheumatoid arthritis. 
   
   
       18 . A pharmaceutical kit according to  claim 16 , comprising instructions for use in the treatment of endotexemia. 
   
   
       19 .- 22 . (canceled)